Wednesday, January 15, 2025 1/15/2025

Theory and Modeling of Noncovalent Binding

Award Number: R01GM061300
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary Identifying a small molecule that tightly binds a targeted protein is a time-consuming, costly step in many drug discovery projects. Explicit solvent free energy methods can be used to predict small molecule-protein binding affinities and thus assist with this step. However, they do not provide consistently accurate predictions, and limitations in the force fields they use are implicated as a key source of error. Our main goal, therefore, is to help generate more trustworthy force fields. In particular, we aim to prove principle for the use of experimental binding data for host-guest systems, along with traditionally used liquid properties, to refine force field parameters. We also aim show that free energy methods can help predict ligand binding poses and rank compound libraries against targeted proteins. First, we will expand the chemical diversity of host-guest systems, by developing facile methods of derivatizing cyclodextrin host molecules, and using these methods to create new, water- soluble cyclodextrin derivatives. We will measure their binding free energies and enthalpies with varied guest molecules, and will use these new data to test and refine force fields. We also aim to prove principle for the use of sensitivity analysis to refine Lennard-Jones (LJ) parameters in existing atom-typed force fields, based on host-guest binding data and liquid property data. In addition to adjusting existing atom-typed parameters, we will develop an atoms-in-molecules approach to mapping a quantum calculation for a molecule to LJ parameters for that molecule. By reducing the number of parameters, relative to atom-typed methods, this approach should enable global parameter optimization, rather than just refinement of existing parameters. Finally, we will automate and optimize our lab’s attach-pull-release (APR) method of computing binding free energies so that it can be used to rank candidate poses of a ligand in a binding site; the most stable few poses will then be used for full binding free energy calculations. Success in this effort will enable free energy methods to be used in virtual compound screening. In addition, we will use the APR method to test the new parameters generated above in the context of protein-ligand binding.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2021	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	21	5/4/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $460,668 )
2021	2021	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	21	8/27/2021	NON-COMPETING CONTINUATION	$402,865
2021	2021	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	001	21	8/31/2021	SUPPLEMENT FOR EXPANSION	$57,803
														Subtotal = $460,668

Issue Date FY: 2020 ( Subtotal = $658,720 )
2020	2020	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	002	20	8/31/2020	SUPPLEMENT FOR EXPANSION	$84,000
2020	2020	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	001	20	8/10/2020	NON-COMPETING CONTINUATION	$517,102
2020	2020	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	19	3/5/2020	SUPPLEMENT FOR EXPANSION	$57,618
														Subtotal = $658,720

Issue Date FY: 2019 ( Subtotal = $401,590 )
2019	2019	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	002	19	8/20/2019	NON-COMPETING CONTINUATION	$401,590
2019	2018	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	001	18	3/11/2019	COMPETING CONTINUATION	$35,868
2019	2017	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	17	3/11/2019	NON-COMPETING CONTINUATION	-$35,868
														Subtotal = $401,590

Issue Date FY: 2018 ( Subtotal = $400,528 )
2018	2018	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	18	8/27/2018	COMPETING CONTINUATION	$400,528
														Subtotal = $400,528

Issue Date FY: 2017 ( Subtotal = $383,706 )
2017	2017	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	17	8/17/2017	NON-COMPETING CONTINUATION	$383,706
														Subtotal = $383,706

Issue Date FY: 2016 ( Subtotal = $370,546 )
2016	2016	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	16	9/9/2016	NON-COMPETING CONTINUATION	$370,546
														Subtotal = $370,546

Issue Date FY: 2015 ( Subtotal = $434,693 )
2015	2015	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	001	15	8/26/2015	NON-COMPETING CONTINUATION	$371,956
2015	2015	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	002	15	9/11/2015	SUPPLEMENT FOR EXPANSION	$62,737
2015	2013	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	13	8/24/2015	NON-COMPETING CONTINUATION	$0
														Subtotal = $434,693

Issue Date FY: 2014 ( Subtotal = $373,215 )
2014	2014	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	14	9/8/2014	COMPETING CONTINUATION	$373,215
														Subtotal = $373,215

Issue Date FY: 2013 ( Subtotal = $358,117 )
2013	2013	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	13	5/31/2013	NON-COMPETING CONTINUATION	$358,117
														Subtotal = $358,117

Issue Date FY: 2012 ( Subtotal = $371,106 )
2012	2012	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	12	5/29/2012	NON-COMPETING CONTINUATION	$371,106
														Subtotal = $371,106

Issue Date FY: 2011 ( Subtotal = $371,106 )
2011	2011	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	11	6/10/2011	NON-COMPETING CONTINUATION	$371,106
														Subtotal = $371,106

Issue Date FY: 2010 ( Subtotal = $362,072 )
2010	2010	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	004	10	6/21/2010	COMPETING CONTINUATION	$374,853
2010	2009	MARYLAND BIOTECHNOLOGY INSTITUTE	701 E PRATT STREET, SUITE 200	BALTIMORE	MD	21202	BALTIMORE CITY	USA	Trans-NIH Recovery Act Research Support	002	8	6/16/2010	SUPPLEMENT FOR EXPANSION	-$38,603
2010	2009	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Trans-NIH Recovery Act Research Support	003	9	6/18/2010	SUPPLEMENT FOR EXPANSION	$39,620
2010	2008	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	001	9	6/3/2010	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$67,351
2010	2008	MARYLAND BIOTECHNOLOGY INSTITUTE	701 E PRATT STREET, SUITE 200	BALTIMORE	MD	21202	BALTIMORE CITY	USA	Biomedical Research and Research Training	000	8	6/2/2010	NON-COMPETING CONTINUATION	-$81,149
														Subtotal = $362,072

Issue Date FY: 2009 ( Subtotal = $81,255 )
2009	2009	MARYLAND BIOTECHNOLOGY INSTITUTE	701 E PRATT STREET, SUITE 200	BALTIMORE	MD	21202	BALTIMORE CITY	USA	Trans-NIH Recovery Act Research Support	000	8	9/30/2009	SUPPLEMENT FOR EXPANSION	$81,255
														Subtotal = $81,255

Issue Date FY: 2008 ( Subtotal = $273,587 )
2008	2008	MARYLAND BIOTECHNOLOGY INSTITUTE	701 E PRATT STREET, SUITE 200	BALTIMORE	MD	21202	BALTIMORE CITY	USA	Biomedical Research and Research Training	000	8	8/28/2008	NON-COMPETING CONTINUATION	$273,587
														Subtotal = $273,587

Issue Date FY: 2007 ( Subtotal = $273,691 )
2007	2007	MARYLAND BIOTECHNOLOGY INSTITUTE	701 E PRATT STREET, SUITE 200	BALTIMORE	MD	21202	BALTIMORE CITY	USA	Biomedical Research and Research Training	000	7	8/23/2007	NON-COMPETING CONTINUATION	$273,691
														Subtotal = $273,691

Issue Date FY: 2006 ( Subtotal = $310,670 )
2006	2006	MARYLAND BIOTECHNOLOGY INSTITUTE	701 E PRATT STREET, SUITE 200	BALTIMORE	MD	21202	BALTIMORE CITY	USA	Biomedical Research and Research Training	000	6	8/23/2006	NON-COMPETING CONTINUATION	$310,670
														Subtotal = $310,670

Issue Date FY: 2005 ( Subtotal = $293,596 )
2005	2005	MARYLAND BIOTECHNOLOGY INSTITUTE	701 E PRATT STREET, SUITE 200	BALTIMORE	MD	21202	BALTIMORE CITY	USA	Biomedical Research and Research Training	000	5	8/8/2005	COMPETING CONTINUATION	$293,596
														Subtotal = $293,596

Issue Date FY: 2003 ( Subtotal = $259,000 )
2003	2003	MARYLAND BIOTECHNOLOGY INSTITUTE	701 E PRATT STREET, SUITE 200	BALTIMORE	MD	21202	BALTIMORE CITY	USA	Cell Biology and Biophysics Research	000	4	8/4/2003	NON-COMPETING CONTINUATION	$259,000
														Subtotal = $259,000

Issue Date FY: 2002 ( Subtotal = $259,000 ) (Continued on the next page)
Grand Total All Awards = $7,214,866

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Theory and Modeling of Noncovalent Binding

Award Number: R01GM061300

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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